Potassium channel inhibitors and method

ABSTRACT

Indanes, benzopyrans and analogues thereof are potassium channel inhibitors and blockers of IKur and have the structure                    
     where A, B, D, Q, X 1 , R, R 1 , X 2  and R 2  are as defined herein. These compounds are useful as antiarrhythmic agents. In addition, a method is provided for preventing cardiac arrhythmia employing the above compounds.

This is a division of U.S. application Ser. No. 09/670,285 filed Sep.25, 2000, now U.S. Pat. No. 6,511,977, which is a division of U.S.application Ser. No. 09/375,955 filed Aug. 17, 1999, now U.S. Pat. No.6,150,356, which claims priority from U.S. Provisional applicationSerial No. 60/098,709 filed Sep. 1, 1998.

FIELD OF THE INVENTION

The present invention relates to indanes and benzopyrans and analoguesthereof which are potassium channel inhibitors and thus are useful asantiarrhythmic agents.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, novel indanes and benzopyransand analogues thereof are provided which are potassium channelinhibitors and have the structure

including pharmaceutically acceptable salts thereof, prodrug estersthereof, and all stereoisomers thereof, wherein

A, B and D are independently selected from CH or N;

X¹ is

 (where n is 1, 2 or 3),

O, NR⁵, S, SO, SO₂

 or

 wherein the hetero atom in each of the above groups is linked to thearomatic ring; (where R³ and R⁴ are independently H, alkyl, arylalkyl orcycloalkyl, or R³ and R⁴ can be taken together with the carbon to whichthey are attached to form a 5 to 8 carbon containing ring; and R⁵ is H,alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);

R is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl,or cycloalkylalkyl;

R¹ is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl,

 (where R^(5a) can be any of the R⁵ groups), cycloalkyl, cycloalkylalkylor

 (where R⁶ and R⁷ are independently selected from H, aryl, alkyl,arylalkyl or cycloalkyl, or R⁶ and R⁷ can be taken together with thenitrogen atom to which they are attached to form a 5 to 8 memberedring); or R and R¹ can be taken together with the —N—S— atoms to form a5- to 8-membered ring;

X² is a single bond,

 or —O— (where R⁸ is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl orcycloalkylalkyl);

R² is H, alkyl, arylalkyl,

 or

 (where R¹⁰ and R¹¹ are independently selected from H, alkyl, arylalkyl,or cycloalkyl, or R¹⁰ and R¹¹ can be taken together with the nitrogen towhich they are attached to form a 5- to 8-membered ring); and

Q is

 or R²-heterocycle (where R¹² is alkyl, arylalkyl, aryl,

 heterocycle, heterocycloalkyl,

 (where R¹⁴ can be any of the R⁸ groups), alkoxy, CF₃, aryloxy,arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R¹⁵ and R¹⁶ areindependently selected from H, alkyl, arylalkyl, aryl, heterocyclo,cycloalkyl, amino, aminoalkyl, or heterocycloalkyl, or R¹⁵ and R¹⁶ canbe taken together with the nitrogen to which they are attached to form a5- to 8-membered ring which may optionally contain an additionalnitrogen atom in the ring and/or an amino group or an aminoalkyl groupattached to the ring); and

R¹³ is

 (wherein this moiety is as defined with respect to R¹²).

Preferred com;pounds of formula I of the invention can have thefollowing structural formulae:

Preferred are compounds of formula I wherein Q is

 or

 wherein heterocycle is a monocyclic ring (cycloheteroalkyl ring orheteroaryl ring) containing 5 or 6 ring members which include one or twonitrogen atoms in the ring and/or one oxygen atom in the ring.

Also preferred are compounds of formula I where

R is H;

R¹ is aryl or alkyl;

X² is O or a single bond;

R² is H;

X¹ is

 or

 where R³ and R⁴ are each H and/or alkyl;

A and B are each CH;

D is N or CH; and

Q is

 or

 where R¹⁵ and R¹⁶ are H, aryl, aralkyl or aminoalkyl.

Still more preferred are compounds of formula I where

R is H;

R¹ is aryl;

X² is O or a single bond;

R² is H;

X¹ is

 or

X¹ is

A and B are each CH;

D is N or CH; and

Q is

 or

In addition, in accordance with the present invention, a method forpreventing, inhibiting or treating cardiac arrhythmia, including atrialarrhythmia, is provided, wherein a compound of formula I is administeredin a therapeutically effective amount which inhibits the IKur potassiumchannel.

The formula I compound employed in the above method has the structure

including pharmaceutically acceptable salts thereof, prodrug estersthereof, and all stereoisomers thereof, wherein

A, B and D are independently selected from CH or N;

X¹ is

 (where n is 1, 2 or 3),

O, NR⁵, S, SO, SO₂,

 or

 wherein the heteroatom in each of the above groups is linked to thearomatic ring;

(where R³ and R⁴ are independently H, alkyl, arylalkyl or cycloalkyl, orR³ and R⁴ can be taken together with the carbon to which they areattached to form a 5 to 8 carbon containing ring; and R⁵ is H, alkyl,alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);

R is H, alkyl, alkenyl, aryl, arylalkyl, heterocycloalkyl, cycloalkyl,or cycloalkylalkyl;

R¹ is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl,

 (where R^(5a) can be any of the R⁵ groups), cycloalkyl, cycloalkylalkylor

 (where R⁶ and R⁷ are independently selected from H, aryl, alkyl,arylalkyl or cycloalkyl, or R⁶ and R⁷ can be taken together with thenitrogen atom to which they are attached to form a 5 to 8 memberedring); or R and R¹ can be taken together with the —N—S— atoms to form a5- to 8-membered ring;

X² is a bond,

 or —O— (where R⁸ is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl orcycloalkylalkyl);

R² is H, alkyl, arylalkyl,

 or

 (where R¹⁰ and R¹¹ are independently selected from H, alkyl, arylalkylor cycloalkyl, or R¹⁰ and R¹¹ can be taken together with the nitrogen towhich they are attached to form a 5- to 8-membered ring); and

Q is

 or R¹²-heterocycle (where R¹² is alkyl, arylalkyl, aryl,

 heterocycle, heterocycloalkyl,

 where R¹⁴ can be any of the R⁸ groups), alkoxy, aryloxy, arylalkoxy,cycloalkyl or cycloalkylalkyl, and where R¹⁵ and R¹⁶ are independentlyselected from H, alkyl, arylalkyl, heterocyclo, cycloalkyl orheterocycloalkyl, or R¹⁵ and R¹⁶ can be taken together with the nitrogento which they are attached to form a 5- to 8-membered ring (which mayoptionally contain an additional nitrogen in the ring and/or an aminogroup or an aminoalkyl group attached to the ring); and

R¹³ is

 (wherein this moiety is as defined with respect to R¹²).

DETAILED DESCRIPTION OF THE INVENTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 40 carbons, preferably1 to 20 carbons, more preferably 1 to 12 carbons, in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousadditional branched chain isomers thereof, and the like as well as suchgroups including 1 to 4 substituents which may be halogen, haloalkyl,alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,cycloalkenyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonylamino, acyl, nitro, cyano,thiol,alkylthio or any of the alkyl or aryl substituents set out herein.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 4 to 12 carbons, forming the ring and which may be fused toone aromatic ring as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents which may be any of the alkyl or aryl substituents set outherein.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to cyclic hydrocarbons containing 5 to 20 carbons,preferably 6 to 12 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may optionally include one to threeadditional rings fused to a carbocyclic ring or a heterocyclic ring(such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and maybe optionally substituted through available carbon atoms with 1, 2, or 3groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl,alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl,heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio,arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl,heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino whereinthe amino includes 1 or 2 substituents (which are alkyl, aryl or any ofthe other aryl compounds mentioned in the definitions), thiol,alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,arylsulfonylamino or arylsulfonaminocarbonyl.

The term “aralkyl”, “aryl-alkyl” or “aryllower alkyl” as used hereinalone or as part of another group refers to alkyl groups as discussedabove having an aryl substituent, such as benzyl or phenethyl, ornaphthylpropyl, or an aryl as defined above.

The term “lower alkoxy”, “alkoxy”, “aryloxy” or “aralkoxy” as employedherein alone or as part of another group includes any of the abovealkyl, aralkyl or aryl groups linked to an oxygen atom.

The term “amino” as employed herein alone or as part of another groupmay optionally be independently substituted with one or twosubstituents, which may be the same or different, such as alkyl, aryl,arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid or any of the alkyl oraryl substituents set out above. In addition, the amino substituents maybe taken together with the nitrogen atom to which they are attached toform 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

The term “lower alkylthio”, alkylthio”, “arylthio” or “aralkylthio” asemployed herein alone or as part of another group includes any of theabove alkyl, aralkyl or aryl groups linked to a sulfur atom.

The term “lower alkylamino”, “alkylamino”, “arylamino”, or“arylalkylamino” as employed herein alone or as part of another groupincludes any of the above alkyl, aryl or arylalkyl groups linked to anitrogen atom.

The term “acyl” as employed herein by itself or part of another group,as defined herein, refers to an organic radical linked to a carbonyl

group; examples of acyl groups include any of the R¹ groups attached toa carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

The term “alkanoyl” as used herein alone or as part of another grouprefers to alkyl linked to a carbonyl group.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkenyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonyl-amino, acyl, nitro, cyano,thiol, alkylthio or any of the alkyl or aryl substituents set outherein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,4-dodecynyl and the like, and which may be optionally substituted with 1to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, or any of the alkyl or arylsubstituents set out herein.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

Suitable alkylene, alkenylene or alkynylene groups (CH₂)_(p) (where p is1 to 8, preferably 1 to 5) (which may include alkylene, alkenylene oralkynylene groups) as defined herein, may optionally include 1, 2, or 3substituents which include any of the alkyl or aryl substituents set outherein.

Examples of alkylene, alkenylene and alkynylene include

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or fluorine being preferred.

The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

The term “heterocycle” or “heterocyclo” as used herein alone or as partof another group refers to a “cycloheteroalkyl” group or a “heteroaryl”group as defined hereinafter.

The term “heterocycloalkyl” as used herein alone or as part of anothergroup refers to a heterocycle linked through a carbon to an alkyl group.

The term “cycloheteroalkyl” as used herein alone or as part of anothergroup refers to a 5-, 6- or 7-membered saturated or partiallyunsaturated ring which includes 1 to 2 hetero atoms such as nitrogen,oxygen and/or sulfur, linked through a carbon atom or a heteroatom,where possible, optionally via the linker (CH₂)_(p) (which is definedabove), such as

and the like. The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of the alkyl or aryl substituents set outherein. In addition, any of the above rings can be fused to acycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

The term “heteroaryl” as used herein alone or as part of another grouprefers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4hetero atoms such. as nitrogen, oxygen or sulfur, and such rings fusedto an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g.benzothiophenyl, indolyl), and includes possible N-oxides. Theheteroaryl group may optionally include 1 to 4 substituents such as anyof the alkyl or aryl substituents set out above. Examples of heteroarylgroups include the following:

and the like.

The term “cycloheteroalkylalkyl” as used herein alone or as part ofanother gorup refers to cycloheteroalkyl groups as defined above linkedthrough a C atom or heteroatom to a (CH₂)_(p) chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to a —(CH₂)_(p)— chain,alkylene or alkenylene as defined above.

The term “polyhaloalkyl” as used herein refers to an “alkyl” group asdefined above which includes from 2 to 9, preferably from 2 to 5, halosubstituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃ orCF₃CF₂CH₂.

The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such asCF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

The compounds of formula I can be present as salts, in particularpharmaceutically acceptable salts. If the compounds of formula I have,for example, at least one basic center, they can form acid additionsalts. These are formed, for example, with strong inorganic acids, suchas mineral acids, for example sulfuric acid, phosphoric acid or ahydrohalic acid, with strong organic carboxylic acids, such asalkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted orsubstituted, for example, by halogen, for example acetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonicacids which are unsubstituted or substituted, for example by halogen,for example methane- or p-toluene-sulfonic acid. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds of formula I having at least oneacid group (for example COOH) can also form salts with bases. Suitablesalts with bases are, for example, metal salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium or magnesiumsalts, or salts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-loweralkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-,triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- ortrihydroxy lower alkylamine, for example mono-, di- or triethanolamine.Corresponding internal salts may furthermore be formed. Salts which areunsuitable for pharmaceutical uses but which can be employed, forexample, for the isolation or purification of free compounds I or theirpharmaceutically acceptable salts, are also included.

A preferred salt of the compounds of formula I is the monohydrochloridesalt.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

It should be understood that the present invention includes prodrugforms of the compounds of formula I such as alkylesters of acids or anyof the prodrugs disclosed in “Prodrugs”, D. G. Waller, C. F. George, Br.J. Clin. Pharmac. (1989), 28, 497-507; “Prodrugs for the improvement ofdrug absorption via different routes of administration”, L. P. Balant,E. Doelker, P. Burt, Eur. J. Drug Metab. Pharmacokinet. (1990), 15,143-153; “Prodrugs as a means to improve the delivery of peptide drugs”,H. Bundgaard, Advanced Drug Delivery Reviews (1992), 8, 1-38; “Novelchemical approaches in prodrug design”(1991), Drugs of the Future, 16,443-458; and in U.S. application Ser. No. 08/641,718, filed May 2, 1996,and in U.S. Pat. No. 5,561,146 which are incorporated herein byreference.

The compounds of the instant invention may, for example, be in the freeor hydrate form, and may be obtained by methods exemplified by thefollowing descriptions.

The compounds of formula I may be prepared by the exemplary processesdescribed in the following reaction schemes. Exemplary reagents andprocedures for these reactions appear hereinafter and in the workingExamples.

Compounds of formula I of the invention can be prepared by using thesequence of steps outlined in General Schemes 1 to 8 set out below.

Referring to General Scheme 1, amide compounds of the invention offormula IA may be prepared starting with nitrile II which is made toundergo a sulfonylation by reacting II with a sulfonylating agent III(employing a molar ratio of III:II within the range from about 1:1 toabout 10:1) in the presence of a base such as triethylamine ordiisopropylethylamine in an inert organic solvent such as acetonitrileand/or dichloromethane, to form sulfonylated compound IV.

Compound IV is then subjected to nitrile hydrolysis by treating anaqueous solution of IV with sodium peroxide and then with strong acidsuch as hydrochloric acid, to form the acid V.

Acid V is treated with amine VI (employing a molar of VI:V within therange from about 1:1 to about 10:1) and a dehydrating agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide with4-dimethylaminopyridine in the presence of an inert solvent such asacetonitrile and/or dimethylformamide, to form amide compounds of theinvention IA.

The starting nitrile II in General Scheme 1 may be prepared as describedin K. Atwal et al, J. Med. Chem. (1993) 36, 3971-3974 and referencescited therein.

Referring to General Scheme 2, compounds of the invention of formula IBmay be prepared from acid V employing methods known in the literatureand described in “Comprehensive Heterocyclic Chemistry”, A. Katritsky etal, Pergamon, Elsevier Science, Inc., (1996).

Where F is oxygen and E and G are nitrogen, compound IB may be preparedby reaction of the acid V with a hydroxyamidine in the presence of adehydrating agent such as(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(P_(y)BOP) and a tertiary amine such as triethylamine in an inertorganic solvent such as dichloromethane. The resultingacylhydroxyamidine can be treated with a base such as potassium, sodiumor cesium carbonate in an inert organic solvent such as tetrahydrofuranto provide compound IB.

Referring to General Scheme 3, compounds of the invention of formula ICwhere either R¹⁵ or R¹⁶ is aryl may be prepared starting with compound Xwhich is made to undergo sulfonylation by reacting nitro compound X withsulfonylating agent III (employing a molar ratio of III:X within therange from about 1:1 to about 10:1) in the presence of a base such astriethylamine and an inert organic solvent such as dichloromethane toform sulfonylated compound XI.

Compound XI is reduced, for example, by reacting XI with KBH₄ in thepresence of CuCl to form aniline XII. Aniline XII is then subjected tocyanoguanidine formation by reacting XII with an N-cyanothiourea sodiumsalt XIII (employing a molar ratio of XIII:XII within the range fromabout 1:1 to about 5:1), in the presence of a carbodiimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and an inert organicsolvent such as anhydrous dimethylformamide, dichloromethane oracetonitrile to form cyanoguanidine of the invention IC.

The starting nitro compound X may be prepared following procedures asdescribed in WO9804521.

The sodium salt of a cyanothiourea XIII may be prepared from thecorresponding isothiocyanate and cyanamide as described in Atwal, K. S.;Ahmed, S. Z., O'Reilly, B. O. Tetrahedron Letters (1989) 30, 7313.

Referring to General Scheme 4, compounds of the invention of formula IDwhere R¹⁵ and R¹⁶ are alkyl may be prepared starting with anilinecompound XII which is reacted with diphenyl cyanocarbonimidate XI V(employing a molar ratio of XIV:XII within the range from about 1:1 toabout 5:1) in an inert organic solvent such as acetonitrile under refluxconditions to form cyanoimidate XV.

Cyanoimidate XV is then reacted with amine XVI (employing a molar ratioof XVI:XV within the range from about 1:1 to about 5:1) in the presenceof inert organic solvents such as isopropanol and dimethylsulfoxide toform cyanoguanidine compound of the invention ID.

Referring to General Scheme 5, compounds of the invention of.the formulaIE may be prepared by starting with nitrile II which is made to undergonitrile hydrolysis with concentrated aqueous acid such as hydrochloric,hydrobromic or sulfuric acid to form the amino acid XVIII.

The amino acid XVIII may be protected using an amine protecting reagentsuch as di-t-butyldicarbonate (or other suitable reagents described inTheodora Greene, Peter Wuts “Protective Groups in Organic Synthesist”2nd Ed. Wiley-Interscience, 1991) in water with an organic cosolventsuch as t-butanol and a water soluble base such as sodium hydroxide orsodium bicarbonate to give the acid XIX.

The acid XIX is treated with amine VI (employing a molar ratio of XIX:VIwithin the range from about 1:1 to about 1:10) and a dehydrating agentsuch as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and orbromo-tris-pyrrolidinophosphonium hexafluorophosphate in the presence ofan organic base such as N,N-diisopropylethylamine or triethylamine in aninert solvent such as acetonitrile and/or dimethylformamide to form theamide XXI.

The amide XXI may be deprotected using the reagent appropriate for theprotecting group used, for example, hydrogen chloride in an inertorganic solvent such as dioxane, methanol or ethyl acetate for removalof the t-butyloxycarbonyl group, to form the amine XXII.

The amine XXII may be sulfonylated by reaction with a sulfonylatingagent III (employing a molar ratio of XXII:III within the range fromabout 1:1 to about 1:10) in the presence of an organic base such asN,N-diisopropylethylamine or triethylamine in an inert organic solventsuch as acetonitrile, N,N-dimethylformamide, dichloromethane ordichloroethane to form compounds of the invention IE.

The starting nitrile II in General Scheme 5 can be prepared as describedin the references cited in General Scheme 1.

Referring to General Scheme 6, compounds of the invention IF may beprepared starting from the sulfonyl chloride XXIII which may be reactedwith an amine VI (employing a molar ratio of XXIII:VI within the rangefrom about 1:1 to about 1:10) in the presence of an organic base such asN,N-diisopropylethylamine or triethylamine in an inert organic solventsuch as acetonitrile, N,N-dimethylformamide, dichloromethane ordichloroethane to form compounds of the formula XXIV.

The sulfonamide XXIV may be epoxidized using an epoxidizing agent suchas m-chloroperbenzoic acid or dimethyldioxirane in an inert organicsolvent such as dichloromethane or acetone to form the epoxide XXV.

The epoxide XXV may be opened by reaction with concentrated aqueousammonia either neat or with an organic cosolvent such as methanol orethanol to form the aminoalcohol XXVI.

The aminoalcohol XXVI may be sulfonylated by reaction with asulfonylating agent III (employing a molar ratio of XXVI:III within therange from about 1:1 to about 1:10) in the presence of an organic basesuch as N,N-diisopropylethylamine or triethylamine in an inert organicsolvent such as acetonitrile, N,N-dimethylformamide, dichloromethane ordichloroethane to form compounds of the invention IF.

An example of a sulfonyl chloride XXII in General Scheme 6 can beprepared as described in Ding, C Z. Synthetic Comm. 1996, 26, 4267-4273.

Referring to General Scheme 7, compounds of the invention of formula IGmay be prepared starting from bromide XXVII which may be metallated witht-butyllithium in an inert organic solvent such as tetrahydrofuran andthe anion reacted with an acylating agent such as ethylchloroformate toform the ester XXVIII.

The ester XXVIII may react with epoxide forming reagents such asN-bromosuccinimide followed by base treatment, m-chloroperbenzoic acid,or dimethyldioxirane to form the epoxide XXIX.

The epoxide XXIX may be opened by reaction with concentrated aqueousammonia either neat or with an organic cosolvent such as methanol orethanol to form the aminoalcohol XXX.

The aminoalcohol XXX may be sulfonylated by reaction with asulfonylating agent III (employing a molar ratio of XXXII:III within therange from about 1:1 to about 1:10) in the presence of an organic basesuch as N,N-diisopropylethylamine or triethylamine in an inert organicsolvent such as acetonitrile, N,N-dimethylformamide, dichloromethane ordichloroethane to form the sulfonamide XXXI.

The ester in compound XXXI may be hydrolyzed using a base such aspotassium hydroxide, sodium hydroxide or lithium hydroxide in aqueoussolution or in water with an organic cosolvent such as methanol,ethanol, ethylene glycol or dioxane to form the acid XXXII.

The acid XXXII may be treated with amine VI (employing a molar ratio ofXIX:VI within the range from about 1:1 to about 1:10) and a dehydratingagent such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and orbromo-tris-pyrrolidinophosphonium hexafluorophosphate in the presence ofan organic base such as N,N-diisopropylethylamine or triethylamine in aninert solvent such as acetonitrile and/or dimethylformamide to formcompounds of the invention IG.

An example of a bromide XXVII in General Scheme 7 where A and B are CHand D is N can be prepared as described in Barger, T. M.; Dulworth, J.K.; Kenny, M. T.; Massad, R.; Daniel, J. K.; Wilson, T.; Sargent, R. N.;J. Med. Chem., 1986, 29, 1590 and Evans, J. M.; Stemp, G.; Syn. Comm.,1988, 18, 1111.

Referring to General Scheme 8, compounds of the invention IH may beprepared from the amine XXII by derivatization of the amine using analkylating agent such as an alkyl halide or by reductive alkylationusing an aldehyde and a suitable reducing agent such as sodiumcyanoborohydride, sodium triacetoxyborohydride or borane-pyridinecomplex in an organic solvent such as methanol, ethanol or acetic acidto form the amine compound XXXIII.

The amine compound XXXIII may be sulfonylated by reaction with asulfonylating agent III (employing a molar ratio of XXXIII:III withinthe range from about 1:1 to about 1:10) in the presence of an organicbase such as N,N-diisopropylethylamine or triethylamine in an inertorganic solvent such as acetonitrile, N,N-dimethylformamide,dichloromethane or dichloroethane to form compounds of the invention IH.

Amine compounds XXII in General Scheme 8 have previously been describedin General Scheme 5.

In the above Schemes, although the Q moiety is fixed at a definiteposition in the aromatic ring, it will be understood that the Q moietymay be attached at any appropriate position on the aromatic ring.

The compounds of formula I of the invention exhibit potassium channelinhibitory activity. They are blockers of the delayed rectifiervoltage-gated potassium channel termed IKur which has been reported tocontain the voltage gated potassium channel Kv 1.5 α-subunit geneproduct. This gene product is believed to be important in therepolarization of the human atrial action potential. The compounds ofthe invention are useful in the treatment of cardiac arrhythmiaespecially those occurring in the atria as well as in cell proliferativedisorders, such as leukemia and autoimmune diseases such as rheumatoidarthritis and transplant rejection.

Thus, compounds of formula I of the invention may be used asantiarrhythmic agents, i.e., for the prevention or treatment ofarrhythmia including atrial arrhythmia. Thus, a composition containingone (or a combination) of the compounds of this invention, may beadministered to a species of mammal (e.g., humans, dogs or cats)suffering from an arrhythmic condition.

A single dose, or two to four divided daily doses, provided on a basisof about 0.001 to about 100 mg per kilogram of body weight per day,preferably about 0.1 to about 25 mg per kilogram of body weight per dayis appropriate. The substance is preferably administered orally, butparenteral routes such as the subcutaneous, intramuscular, intravenousor intraperitoneal routes or any other suitable delivery system, such asintranasal or transdermal routes can also be employed.

The compounds of this invention can also be formulated in combinationwith a cyclooxygenase inhibitor such as aspirin or indomethacin, aplatelet aggregation inhibitor such as clopidogrel, ticlopidene oraspirin, fibrinogen antagonists or a diuretic such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorthiazide, trichloromethiazide,polythiazide or benzthiazide as well as ethacrynic acid tricrynafen,chlorthalidone, furosemide, musolimine, bumetanide, triamterene,amiloride and spironolactone and salts of such compounds, angiotensinconverting enzyme inhibitors such as captopril, zofenopril, fosinopril,enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril,ramipril, lisinopril, and salts of such compounds, angiotensin IIantagonists such as losartan, irbesartan or valsartan, thrombolyticagents such as tissue plasminogen activator (tPA), recombinant tPA,streptokinase, urokinase, prourokinase, and anisoylated plasminogenstreptokinase activator complex (APSAC, Eminase, Beecham Laboratories),or animal salivary gland plasminogen activators, calcium channelblocking agents such as verapamil, nifedipine or diltiazem, thromboxanereceptor, antagonists such as ifetroban, prostacyclin mimetics, orphosphodiesterase inhibitors. Such combination products if formulated asa fixed dose employ the compounds of this invention within the doserange described above and the other pharmaceutically active agent withinits approved dose range.

The compounds of formula I, and combinations thereof, can be formulated,as described above, in compositions such as tablets, capsules or elixirsfor oral administration, in sterile solutions or suspensions forparenteral administration, and may also be administered via transdermalpatch or nasal inhalation solutions. About 10 to about 500 milligrams ofa compound of formula I is compounded with physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, flavor,etc., in a unit dosage form as called for by accepted pharmaceuticalpractice. The amount of active substance in these compositions orpreparations is such that a suitable dosage in the range indicated isobtained.

The following examples and preparations describe the manner and processof making and using the invention and are of preferred embodiments ofthe invention, which include compounds of the invention and compoundsemployed in the method of the invention. It should be understood thatthere may be other embodiments which fall within the spirit and scope ofthe invention as defined by the claims appended hereto.

EXAMPLE 1

trans-4-Amino-3,4-dihydro-2,2-dimethyl-6-cyano-2H-benzopyran

The title compound is prepared as described in K. Atwal et al, J. Med.Chem. (1993) 36, 3971-3974 and references cited therein.

Part A compound(trans-4-Amino-3,4-dihydro-2,2-dimethyl-6-cyano-2H-benzopyran) (5100 mg,17.8 mmol) and triethylamine (2100 mg; 20.8 mmol) were dissolved in 50mL of dichloromethane and cooled to 0° C. 4-Ethylbenzenesulfonylchloride (3930 mg, 19.2 mmol) in 20 mL of dichloromethane was addeddropwise and the reaction was stirred for 1 hour. The pH was thenadjusted to 7 with 300 uL of triethylamine. After 1 additional hour thereaction was diluted with dichloromethane (100 mL) and washed with water(30 mL), saturated aqueous ammonium chloride (20 mL) and brine (50 mL).The organic phase was dried over magnesium sulfate, filtered and thesolvent removed to provide 5.84 g (85%) of an off-white solid. The solidwas used in the next reaction without further purification. LCMS-84% at3.7 min (YMC S5 C18 4.6×50 mm Ballistic Column) 10-90% MeOH/Water with0.2% TFA linear gradient over 4 min, 4 mL/min UV Detection at 220 nm,M+H 387.0.

Part B benzopyran (5800 mg, 15 mmol) was added to 200 mL of water withsodium peroxide (5860 mg, 75 mmol) and all the solid dissolved. Thesolution was heated at 60° C. for 48 hours. Sodium peroxide (2000 mg, 26mmol) was added and the solution heated for 72 hours. The reaction wasacidified by addition of hydrochloric acid (100 mL, 1.0 M, aq.). Themixture was extracted with ethyl acetate (3×75 mL) and the organic phasewashed with brine (50 mL) and dried over magnesium sulfate, filtered andthe solvent removed to yield 6 g of an off white solid. Purification byflash chromatography on silica gel eluted with 7% methanol,dichloromethane yielded 2.0 g (33%) of title compound in the form of awhite solid. HPLC-96% at 3.6 min (YMC S5 C18 4.6×50 mm Ballistic Column)10-90% MeOH/Water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/minUV Detection at 220 nm, ¹H NMR (270 MHz, CDCl₃) ¹³C NMR (68 MHz, CDCl₃).

1,2,3,4-Tetrahydro-1-naphthalamine (10.6 mg, 0.072 mmol) was weighedneat into a 16×100 mm test tube. The Part C acid (24.3 mg, 0.06 mmol)was dissolved in 1 mL of acetonitrile with 50 uL of dimethyl formamide.4-Dimethylaminopyridine (100 uL of a 0.06M soln in MeCN) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 mL of a0.06 M soln in MeCN) were added and the tube was shaken on a vortexmixer overnight. The reaction was loaded onto a strong cation exchangesolid phase extraction cartridge (CUBCX 12M6 SPE, 2 g, 6 mL) that hadbeen conditioned by elution with two 10 mL portions of methanol. Thecartridge was eluted with 20 mL of 25% methanol/dichloromethane and thesolvent removed to provide 25 mg (78%) of a tan solid. HPLC analysisshowed 68% of a major product which was purified by reverse phase HPLC(YMC S5 C18 20×100 mm Column) 50-90% MeOH/Water with 0.1% TFA lineargradient over 10 min, 20 mL/min UV detection at 220 nm). The relevantfraction was collected and dried in vacuo to give 18.4 mg (51%) of titlecompound in the form of a white solid. HPLC-97% at 2.0 min (Phenom-LUNAS5 C18 4.6×30 mm column) 50-90% MeOH/Water with 0.2% H₃PO₄ lineargradient over 2 min, 5 mL/min UV detection at 220 nm; ¹H NMR (400 MHz,CD₃OD).

EXAMPLES 2-4

The following compounds were synthesized by the procedures described inExample 1.

Example Structure Mass spec m/z 2

495 (M + H) 3

509 (M + H) 4

481 (M + H)

EXAMPLE 5

Example 1 Part C acid (24.3 mg, 0.06 mmol) was dissolved in 1 mL ofacetonitrile in a 16×100 mm test tube with heating (steam bath).2,4-Difluoroaniline (8.1 mg, 0.066 mmol) and1-hydroxy-7-azabenzotriazole (9.0 mg, 0.072 mmol) were added to producea slurry. 1-(3-Dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride(9.3 mg, 0.066 mmol) in 1 ml of acetonitrile was added and alldissolved. The tube was heated, for 6 days at 60° C. in a sand bath andwas loaded directly onto a strong cation exchange solid phase extractioncartridge (CUBCX 12M6 SPE, 2 g, 6 mL) that had been conditioned byelution with two 10 mL portions of methanol, followed by 10 mL ofacetonitrile. The cartridge was eluted with 10 mL of 5%methanol/acetonitrile and relevant fraction was collected and dried invacuo to give 30 mg (97%) of a white solid. HPLC-MS analysis showed 51%of the desired product and 43% of a product consistent with the1-hydroxy-7-azabenzo-triazole (HOAt) ester of the starting acid. Themixture was purified by derivitizing the remaining HOAt ester withN-phenylethylenediamine (4 uL, 0.03 mmol) in 1 ml of acetonitrile. Thereaction was shaken on a vortex mixer for 12 hours and was loadeddirectly onto a strong cation exchange solid phase extraction cartridge(CUBCX 12M6 SPE, 2 g, 6 mL) that had been conditioned by elution withtwo 10 mL portions of methanol then 10 mL acetonitrile. The cartridgewas eluted with 10 mL of 5% methanol/acetonitrile and relevant fractionwas collected and dried in vacuo to give 17.7 mg (57%) of the desiredtitle product as a white solid. HPLC-89% at 2.8 min (YMC S5 C18 4.6×50mm Ballistic Column) 10-90% MeOH/Water with 0.2% H₃PO₄ linear gradientover 4 min, 4 mL/min UV detection at 220 nm. ¹H NMR (400 MHz, CD₃OD)42763-038-18, ¹³C NMR (68 MHz, CD₃OD).

EXAMPLES 6 TO 41

The following compounds were synthesized using the procedure describedin Example 5.

Example Structure Mass spec m/z  6

525 (M + H)  7

569 (M + H)  8

487 (M + H)  9

525 (M + H) 10

511 (M + H) 11

560 (M + H) 12

525 (M + H) 13

495 (M + H) 14

525 (M + H) 15

509 (M + H) 16

537 (M + H) 17

593 (M + H) 18

509 (M + H) 19

565 (M + H) 20

551 (M + H) 21

525 (M + H) 22

539 (M + H) 23

587 (M + H) 24

535 (M + H) 25

571 (M + H) 26

567 (M + H) 27

617 (M + H) 28

511 (M + H) 29

647 (M + H) 30

557 (M + H) 31

585 (M + H) 32

523 (M + H) 33

588 (M + H) 34

545 (M + H) 35

549 (M + H) 36

642 (M + H) 37

589 (M + H) 38

621 (M + H) 39

495 (M + H) 40 and 41

484 (M + H)

EXAMPLE 42

Example 1 Part C benzopyran acid (1000 mg, 2.5 mmol) was combined withtetramethylfluoroformamidinium hexaflurophosphate (660 mg 2.5 mmol) andtriethylamine (522 ul, 3.75 mmol) in dichloromethane and all the solidsdissolved. After 15 min the solvent was evaporated and the crude solidwas partially redissolved in 2:1 hexane:ethyl acetate and the slurry wasplaced directly on a silica gel column. The column was eluted with 2:1,hexane:ethyl acetate and relevent fractions were combined to give 740 mg(74%) of a white crystaline solid.

Part A acid fluoride (20.4 mg, 0.05 mmol),N-(2-aminoethyl)-N-ethyl-m-toluidine (8.9 mg, 0.05 mmol) andtriethylamine (10.4 ul, 0.075 mmol) were dissolved in 1 mL ofacetonitrile in a 16×100 mm test tube and shaken on a vortex mixer.After 15 minutes the contents of the tube was loaded directly onto astrong cation exchange solid phase extraction cartridge (CUBCX 12M6 SPE,2 g, 6 mL) that had been conditioned by elution with two 10 mL portionsof methanol. The cartridge was eluted with 20 mL of methanol which wasdiscarded. The cartridge was then eluted with 10 mL of 1 N ammonia inmethanol and the relevant fraction was collected and dried in vacuo togive 28.5 mg (100%) of title compound in the form of a white solid.HPLC-94% at 3.6 min (YMC S5 C18 4.6×50 mm Ballistic Column) 10-90%MeOH/Water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UVdetection at 220 nm; LC-MS 93% at 3.6 min (YMC S5 C18 4.6×50 mmBallistic Column) 10-90% MeOH/Water with 0.2% TFA linear gradient over 4min, 4 mL/min UV detection at 220 nm, M+H 566.2. ¹H NMR (400 MHz,CD₃OD).

EXAMPLES 43 TO 107

The following compounds were synthesized using the methods described inExample 42.

Example structure Mass Spec m/z 43

578 (M + H) 44

496 (M + H) 45

552 (M + H) 46

544 (M + H) 47

510 (M + H) 48

510 (M + H) 49

513 (M + H) 50

510 (M + H) 51

496 (M + H) 52

516 (M + H) 53

496 (M + H) 54

516 (M + H) 55

532 (M + H) 56

502 (M + H) 57

564 (M + H) 58

518 (M + H) 59

499 (M + H) 60

545 (M + H) 61

516 (M + H) 62

516 (M + H) 63

518 (M + H) 64

592 (M + H) 65

518 (M + H) 66

552 (M + H) 67

552 (M + H) 68

546 (M + H) 69

566 (M + H) 70

550 (M + H) 71

524 (M + H) 72

580 (M + H) 73

502 (M + H) 74

530 (M + H) 75

590 (M + H) 76

564 (M + H) 77

560 (M + H) 78

551 (M + H) 79

524 (M + H) 80

580 (M + H) 81

502 (M + H) 82

524 (M + H) 83

592 (M + H) 84

578 (M + H) 85

504 (M + H) 86

532 (M + H) 87

504 (M + H) 88

557 (M + H) 89

565 (M + H) 90

555 (M + H) 91

513 (M + H) 92

497 (M + H) 93

511 (M + H) 94

511 (M + H) 95

483 (M + H) 96

502 (M + H) 97

508 (M + H) 98

471 (M + H) 99

499 (M + H) 100 

579 (M + H) 101 

547 (M + H) 102 

557 (M + H) 103 

503 (M + H) 104 

518 (M + H) 105 

502 (M + H) 106 

549 (M + H) 107 

529 (M + H)

EXAMPLE 108

The title hydroxyamidine was synthesized by methods described in J. Med.Chem., 1991, 34, 140-151.

Example 1 Part C benzopyran acid (50 mg, 0.12 mmol) was suspended in 1mL of dichloromethane. Triethylamine (26 μL, 0.19 mmol) and Part Ahydroxyamidine (19 mg, 0.12 mmol) were added followed by(benzotriazol-1-yloxy)-trispyrrolidinophosphonium hexafluorophosphoate(PyBOP) (83 mg, 0.16 mmol). All the solid dissolved upon addition ofPyBOP and the reaction was stirred for 15 hrs. The mixture was dilutedwith ethyl acetate and washed with hydrochloric acid (1.0 M, aq.),sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). Theorganic phase was dried over magnesium sulfate, filtered and the solventremoved to provide 90 mg of a colorless oil. The oil was dissolved in 1mL of tetrahydrofuran, cesium carbonate (88 mg, 0.27 mmol) was addedand-the mixture was heated to 50° for 15 hrs. The reaction was dilutedwith ethyl acetate and washed with hydrochloric acid (1.0 M, aq.),sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). Theorganic phase was dried over magnesium sulfate, filtered and the solventremoved to provide 50 mg of title product in the form of a white solid.Purification by flash chromatography on silica gel eluted with 20%acetone, hexane yielded 30 mg (47%) of a white solid. mp 186-187°; [α]D−137° (CHCl3, c0.45) ¹H NMR (400 MHz, CDCl₃); ¹H NMR (400 MHz,acetone-d⁶); ¹³C NMR (100 MHz, CDCl₃); Mass Spec (ESI).

EXAMPLES 109 TO 111

The following compounds were synthesized by the procedures described inExample 108.

Example Structure Mass Spec m/z 109

506 (M + H) 110

500 (M + H) 111

540 (M + H)

The Part A compound was prepared as described in ICAgen Inc., Lilly &Co. patent application WO9804521-A1 (Preparation 6).

The sodium salt was prepared from the corresponding isothiocyanate andcyanamide by the methods described in K. Atwal et al, J. Med. Chem.(1993), 36, 3971-3974 and references cited therein.

Part A aniline (50 mg, 0.15 mmol) and Part B sodium salt (41 mg, 0.18mmol) were dissolved in 4 mL of anhydrous N,N-dimethylformamide.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg, 0.18mmol) was then added at room temperature and the reaction was stirred atroom temperature under argon for 16 hr. The reaction was thenpartitioned between citric acid (5%, aqueous) and ethyl acetate. Theaqueous phase was extracted with ethyl acetate and the organic extractswere washed with aqueous lithium chloride (10%) , dried over Na₂SO₄,filtered and the solvent removed to provide 81 mg of crude product. Thecrude material was purified by flash chromatography (SiO₂, 13.5 g, 4%methanol, dichloromethane) and the product was concentrated in vacuo andazeotroped several times with a mixture of dichloromethane/hexane toprovide 25 mg (33%) of title compound as a white solid. ¹H NMR (400 MHz,CD₃OD); ¹³C NMR (100 MHz, CD₃OD). ms (ESI). HPLC: 99.1% at 3.6 min (YMCS5 ODS 4.6×50 mm C-18 column, 4 mL/min, 10-90% methanol, water with 0.2%phosphoric acid, linear gradient over 4 min, 2 min hold, UV detection at220 nM).

EXAMPLE 113

Example 112 Part A amine (100 mg, 0.3 mmol) was partially dissolved in 5mL anhydrous acetonitrile and diphenyl cyanocarbonimidate (72 mg, 0.3mmol) was added and the reaction was heated to reflux. The reaction wasrefluxed for 18 hours, then was cooled to room temperature andconcentrated in vacuo to a tan solid which was triturated withdiisopropyl ether and dried in vacuo to provide 145 mg (assumed 100%) ofthe title cyanoimidate as a tan solid. ¹H NMR (270 MHz, CD₃OD+CDCl₃);¹³C NMR (68 MHz, CD₃OD+CDCl₃). ms (ESI).

Part A cyanoimidate (30 mg, 0.063 mmol) was partially dissolved in 2 mLof isopropanol and then benzylamine (21 μL, 0.19 mmol) was added at roomtemperature via syringe. Dimethylsulfoxide (1 mL) was then added to thereaction mixture in order to effect a homogeneous solution. The reactionwas stirred at room temperature under argon for 16 hr. The reaction wasthen concentrated in vacuo and the crude material was purified by flashchromatography (SiO₂, 5 g, 40% acetone, hexane). The product wasconcetrated in vacuo and azeotroped with dichloromethane, hexane toprovide 15 mg (48%) of title compound in the form of a white solid as aracemic mixture. mp 210-217° C. (dec). ¹H NMR (400 MHz, CD₃OD); ¹³C NMR(100 MHz, CD₃OD). ms (ESI). HPLC: 100% at 3.8 min (YMC S5 ODS 4.6×50 mmC-18 column, 10-90% methanol, water with 0.2% phosphoric acid, lineargradient over 4 min, 4 mL/min, UV detection at 220 nM).

EXAMPLE 114 TO 117

The following compounds were synthesized by the procedures described inExample 113.

Example Structure Mass Spec m/z 114

504 115

496 (M + H) 116

524 (M + H) 117

456 (M + H)

EXAMPLE 118

Preparation of A:

trans-4-Amino-3,4-dihydro-2,2-dimethyl-6-cyano-2H-benzopyranmethanesulfonate salt, see Example 1.

Preparation of D:

A mixture oftrans-4-Amino-3,4-dihydro-2,2-dimethyl-6-cyano-2H-benzopyranmethanesulfonate salt (A, 10.0 g, 26.9 mmol) and concentratedhydrochloric acid (100 mL) were refluxed for 9 h. A small aliquot of themixture was partitioned between aqueous sodium hydroxide (1M) and ethylacetate. TLC (10% methanol/dichloromethane) of the ethyl acetate layerindicated consumption of A. The mixture was allowed to cool to roomtemperature and allowed to stand overnight. The white precipitate whichforms is collected by vacuum filtration. The precipitate was washed withhexanes, air dried, dried on a rotary evaporator at 70° C. and finallyunder vacuum to give 8.35 g (113% crude yield) of the title compound Bas white solid. HPLC: 96.9% at 1.92 min. (YMC S5 ODS 4.6×50 mm Ballisticcolumn) 10-90% methanol/water with 0.2% H₃PO₄ linear gradient over 4min., 4 mL/min., UV Detection at 220 nm.

Preparation of C:

Di-tert-butyl dicarbonate (6.8 mL, 34.5 mmol) was added to a roomtemperature solution of B (6.3 g, 23.0 mmol), aqueous sodium hydroxide(100 mL, 1M) and C-butanol (30 mL). The resulting mixture was stirredfor 48 h. A small aliquot of the mixture was partitioned between aqueoushydrochloric acid (1M) and ethyl acetate. TLC (water/ammoniumhydroxide/n-butanol, 1:1:8) of the ethyl acetate layer indicated thereaction was not complete. Additional aqueous sodium hydroxide (20 mL,1M) and di-tert-butyl dicarbonate (3.8 g, 17.2 mmol) were added and themixture was allowed to stir 6 h. TLC indicated the presence of B. Moreaqueous sodium hydroxide (30 mL, 1M) and di-tert-butyl dicarbonate (4.0g, 18.3 mmol) were added and the mixture was allowed to stir overnight.The mixture was transferred to a separatory funnel and washed withhexanes (3×). The hexane extracts were combined and extracted withaqueous sodium hydroxide (1.0 M). The sodium hydroxide portions werecombined and acidified to pH 3 with aqueous hydrochloric acid (1.0 M).The resulting solution was extracted with ethyl acetate. The ethylacetate extracts were combined, washed with aqueous hydrochloric acid(1.0 M), water and brine, dried over anhydrous sodium sulfate andconcentrated to provide 7.7 g (89%) of the title compound C as a yellowfoam. LCMS: 96.4% at 3.23 min. (YMC S5 ODS 4.6×50 mm Ballistic column)10-9.0% methanol/water with 0.1% TFA linear gradient over 4 min., 4mL/min., UV Detection at 220 nm, M+H 338.

Preparation of D:

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.46 g,7.59 mmol) was added to a room temperature solution of C (2.14 g, 6.33mmol), 1-hydroxybenzotriazole hydrate (1.03 g, 7.59 mmol),phenethylamine (0.95 mL, 7.59 mmol) and N-7methylmorpholine (2.1 mL,19.0 mmol) in dimethylformamide (30 mL). After 6 h a small aliquot waspartitioned between aqueous hydrochloric acid (1.0 M) and ethyl acetate.TLC (10% methanol/dichloromethane) indicated consumption of C. Themixture was transferred to a separatory funnel, diluted with ethylacetate, washed with aqueous hydrochloric acid (1.0 M), water andbrine,-dried over anhydrous sodium sulfate and concentrated to give a2.98 g (100%) of the title compound D as a slightly yellow foam ofsufficient purity to be used without further purification. LCMS: 98.9%at 3.82 min. (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%methanol/water with 0.1% TFA linear gradient over 4 min., 4 mL/min., UVDetection at 220 nm, M+H 441.

Preparation of E:

Trifluoroacetic acid (10 mL) was added to a room temperature solution ofD (2.95 g, 6.71 mmol) in dichloromethane (50 mL). After 3 h a smallaliquot was partitioned between aqueous sodium hydroxide (1M) and ethylacetate. TLC (10% methanol/dichloromethane) indicated consumption of D.The reaction was concentrated in vacuo and the residue was partitionedbetween aqueous sodium hydroxide (1.0 M) and ethyl acetate. The mixturewas transferred to a separatory funnel, diluted with ethyl acetate,washed with aqueous sodium hydroxide (1.0 M), water and brine, driedover anhydrous sodium sulfate and concentrated onto enough silica gelsuch that a free flowing powder was obtained. The resulting powder wasloaded onto a chromatography column prepacked with (10%methanol/dichloromethane). Elution with the same solvent provided 1.7 g(77%) of the title compound E as a white foam. LCMS: 98.8% at 3.04 min.(YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% methanol/water with 0.1%TFA linear gradient over 4 min., 4 mL/min., UV Detection at 220 nm, M+H341.

Preparation of F:

4-Chlorobenzenesulfonyl chloride (0.014 g, 0.07 mmol) was added to aroom temperature solution of E (0.012 g, 0.035 mmol) and triethylamine(0.012 mL, 0.088 mmol) in dichloromethane (0.5 mL) in a 16×100 mm testtube. The mixture was shaken gently overnight on a vortex genie. A mixedbed solid phase extraction cartridge (Worldwide Monitoring, CUMBQSP901,containing 1800 mg benzenesulfonic acid “BCX” atop 900 mg quaternaryamine “QAX” with a hydroxide counter ion) was washed with methanol (20mL) followed by dichloromethane (20 mL). The reaction mixture wasdiluted with dichloromethane (0.5 mL) and loaded onto the cartridge. Thecartridge was eluted with dichloromethane (8 mL) collecting 2 fractions,followed by methanol (15 mL) collecting 3 fractions. The fractioncontaining the title compound was concentrated to provide 0.0122 g(68%). HPLC: 100% at 3.12 min. (YMC S5 ODS 4.6×50 mm Ballistic column)40-90% mEthanol/water with 0.2% H₃PO₄ linear gradient over 4 min., 4mL/min., UV Detection at 220 nm. Alternately purification could beperformed by directly loading the reaction mixture onto a preparativeTLC plate (20×20 cm, 1000 micron) and eluting with 5%methanol/dichloromethane to provide the title compound as a whitepowder. LCMS: 89% at 4.03 min. (YMC S5 ODS 4.6×50 mm Ballistic column)10-90% mEthanol/water with 0.1% TFA linear gradient over 4 min., 4mL/min., UV Detection at 220 nm, M+H 515.

The following compounds were synthesized by the procedures described inExample 118.

Example Structure mass spec m/z 119

517 (M + H) 120

447 (M + H) 121

487 (M + H) 122

485 (M + H) 123

481 (M + H) 124

531 (M + H) 125

531 (M + H) 126

583 (M + H) 127

549 (M + H) 128

526 (M + H) 129

571 (M + H) 130

526 (M + H) 131

559 (M + H) 132

499 (M + H) 133

538 (M + H) 134

526 (M + H) 135

511 (M + H) 136

537 (M + H) 137

495 (M + H) 138

539 (M + H) 139

549 (M + H) 140

617 (M + H) 141

583 (M + H) 142

541 (M + H) 143

495 (M + H) 144

549 (M + H) 145

533 (M + H) 146

523 (M + H) 147

595 (M + H) 148

499 (M + H) 149

499 (M + H) 150

565 (M + H) 151

549 (M + H) 152

517 (M + H) 153

515 (M + H) 154

633 (M + H) 155

521 (M + H) 156

549 (M + H) 157

549 (M + H) 158

495 (M + H) 159

529 (M + H) 160

589 (M + H) 161

541 (M + H) 162

549 (M + H) 163

559 (M + H) 164

599 (M + H) 165

529 (M + H) 166

583 (M + H) 167

549 (M + H) 168

559 (M + H) 169

565 (M + H) 170

506 (M + H) 171

506 (M + H) 172

500 (M + H) 173

549 (M + H) 174

583 (M + H) 175

533 (M + H) 176

513 (M + H) 177

545 (M + H) 178

583 (M + H) 179

545 (M + H) 180

554 (M + H) 181

535 (M + H) 182

556 (M + H) 183

517 (M + H) 184

585 (M + H) 185

643 (M + H) 186

506 (M + H) 187

559 (M + H) 188

658 (M + H) 189

559 (M + H) 190

561 (M + H) 191

533 (M + H) 192

635 (M + H) 193

680 (M + H) 194

676 (M + H) 195

649 (M + H) 196

696 (M + H)

EXAMPLE 197

Preparation of A:

See Example 99.

Preparation of B:

Sodium triacetoxyborohydride (0.101 g, 0.47 mmol) was added to a roomtemperature solution of A (0.108 g, 0.32 mmol) in acetic acid (1.0 mL).The resulting mixture was stirred overnight. The mixture was dilutedwith ethyl acetate, made basic (pH 11) with aqueous sodium hydroxide(1M) and stirred for an additional hour. The resulting solution wastransferred to a separatory funnel, washed with aqueous sodium hydroxide(1M), water and brine, dried over anhydrous sodium sulfate andconcentrated. The resulting residue was purified by preparative TLC(20×20 cm, 1000 micron plate) eluting with 5% methanol/dichloromethaneto give 0.055 g (40%) of the title compound B. LCMS: 98.2% at 3.76 min.(YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% mEthanol/water with 0.1%TFA linear gradient over 4 min., 4 mL/min., UV Detection at 220 nm. M+H:431.

Preparation of C:

4-Ethylbenzenesulfonyl chloride (0.38 g, 0.19 mmol) was added to a roomtemperature solution of B (0.53 g, 0.12 mmol) and triethylamine (0.034mL, 0.25 mmol) in dichloromethane (1 mL) and the mixture was stirredovernight. TLC (5% methanol/dichloromethane) indicated the reaction hadnot gone to completion. Additional triethylamine (0.04 mL, 0.28 mmol)and 4-ethylbenzenesulfonyl chloride (0.04 g, 0.16 mmol) were added. TLCafter 5 h indicated most of B was consumed. The mixture was loadeddirectly onto a preparative TLC plate (20×20 cm, 1000 micron) and elutedwith 50% ethyl acetate/hexanes to give 0.608 g (82%) of the titlecompound C. LCMS: 99.5% at 4.34 min. (YMC S5 ODS 4.6×50 mm Ballisticcolumn) 10-90% mEthanol/water with 0.1% TFA linear gradient over 4 min.,4 mL/min., UV Detection at 220 nm. M+H: 599.

The following compounds were synthesized by the procedures described inExample 178.

Example Structure mass spec m/z 198

465 (M + H) 199

565 (M + H) 200

579 (M + H) 201

589 (M + H) 202

600 (M + H) 203

600 (M + H)

EXAMPLE 204

Preparation of A:

The sulfonyl chloride may be prepared by procedures described in Ding,C. Z. Syn. Comm. 1996, 26, 4267-4273 and references cited therein.

Preparation of B:

To a solution of the sulfonyl chloride a (3.9 mmol) in dichloromethane(12 mL) was added triethylamine (7.8 mmol) followed by phenethylamine(5.8 mmol) and the mixture stirred at room temperature overnight afterwhich TLC analysis showed no presence of A. The reaction mixtures wasquenched by addition of 2N aqueous hydrochloric acid and the aqueouslayer extracted with dichloromethane. The organic layers were washedsuccessively with saturated aqueous sodium bicarbonate, brine and driedover magnesium sulfate. Evaporation of the solvent followed bypurification of the residue by column chromatography gave puresulfonamide 3 (87%).

Preparation of C:

To a solution of the sulfonamide B (2.7 mmol) in dichloromethane (20 mL)was added m-chloro-perbenzoic acid (4 mmol, 82% purity with the restbeing benzoic acid) and the mixture stirred at room temperatureovernight when TLC indicated completion of the reaction. The reactionwas quenched with saturated aqueous sodium bicarbonate solution, theorganic layers separated, washed with brine and dried over sodiumsulfate. The solvent was evaporated and the residue carried overdirectly to next step without any purification.

Preparation of D:

The crude epoxy-sulfonamide C was dissolved in a mixture of THF (10 mL),ethanol (10 mL) and ammonium hydroxide solution (28-30%, 20 mL) and thesolution heated in a sealed tube to 45-60° C. until TLC indicated thecomplete consumption of epoxide C (5-6 hrs). The reaction was cooledwhere upon a part of the amino-alcohol D crystallized out. Thecrystallized product was filtered, washed with 10% ethyl acetate-hexaneand air-dried. The washings were combined with the filtrate, the organiclayers separated, dried over sodium sulfate and evaporated. Purificationof the residue by silica gel column chromatography gave additionalamounts of pure amino alcohol D (71%).

Preparation of E:

To a solution of the aminoalcohol D (0.6 mmol) in dichloromethane (5 mL)was added triethyl amine (1.2 mmol) followed by 4-ethylbenzenesulfonylchloride (0.9 mmol) and the mixture stirred at room temperatureovernight when TLC indicated complete consumption of D. The reaction wasquenched with 2N aqueous hydrochloric acid and the aqueous layerextracted with dichloromethane. The combined organic layers were washedsuccessively with saturated aqueous sodium bicarbonate solution, brineand dried over sodium sulfate. Evaporation of the solvent followed bypurification of the residue by silica gel column chromatography gavepure bis-sulfonamide E (82%). Mass Spec (M+H) 545, (2M+NH₄=1106.5); HPLCconditions: Column=YMC S5 C18 4.6×50 mm, solvent=10 to 90% methanol inwater with 0.2% phosphoric acid over a 4 min. gradient, UV detection at220 nm, retention time=4.1 min.

The following compound was synthesized by the procedures described inExample 204.

Example Structure mass spec m/z 205

531 (M + H)

EXAMPLE 206

Preparation of A:

6-Bromo-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine was prepared fromcommercially available 2-Methoxypyridine in 3 steps as described inBarger, T. M.; Dulworth, J. K.; Kenny, M. T.; Massad, R.; Daniel, J. K.;Wilson, T.; Sargent, R. N.; J. Med. Chem., 1986, 29, 1590 and Evans, J.M.; Stemp, G.; Syn. Comm., 1988, 18, 1111.

Preparation of B:

To a vigorously stirred slurry of6-Bromo-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine (A, 3.45 g, 14.4 mmol) inanhydrous ether/toluene (30/60 mL) at −100° C. under inert atmospherewas added a solution of tert-butyl lithium dropwise via syringe (9.8 mL,16.7 mmol, 1.7 M solution in pentane). The slurry was maintained below−70° C. for 1 h then ethylchloroformate (1.6 mL, 16.8 mmol) as addeddropwise and the reaction allowed to reach ambient temperature as thecooling bath warmed. Saturated aqueous sodium bicarbonate (20 mL) wasadded to the yellow slurry and the reaction mixture transferred to aseparatory funnel. The aqueous phase was extracted with ethylacetate(2×50 mL) and the combined organic portions washed successively withsaturated sodium chloride (2×50 mL) and water (50 mL), dried over sodiumsulfate, decanted and concentrated under reduced pressure yielding acrude yellow oil. Purification by flash column chromatography on silicagel using hexane, ethylacetate (6:1) as eluent gave title compound B asa white solid (1.82 g, 50%), HPLC: 91% at 3.64 min. (YMC S5 ODS 4.6×50mm Ballistic column) 10-90% methanol/water with 0.2% H₃PO₄ lineargradient over 4 min., 4 mL/min., UV Detection at 220 nm. HNMR: CDCl₃1.31,t,J=7.2 Hz(3H); 1.47,s(6H); 4.29,q,J=7.1 Hz(2H); 5.65,d,J=9.8Hz(1H); 6.26,d,J=9.8 Hz(1H); 7.79,d,J=2.3 (1H); 8.60,d,J=2.4 Hz(1H).

Preparation of C:

At 20° C., recrystallized N-bromosuccinimide (2.78 g, 15.6 mmol) wasadded in 3 equal portions, 3 minutes apart, to a stirred solution ofethyl-6-carboxy-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine (B, 1.82 g, 7.81mmol) in dimethylsulfoxide/water (27/16 mL). After 3 h the reactionmixture was poured into water (200 mL) and extracted with ethylacetate(3×50 mL). The combined organic portions were washed with saturatedsodium chloride (2×50 mL), dried over sodium sulfate, decanted andconcentrated under reduced pressure yielding a pale yellow solid. Thecrude material was purified by silica gel column chromatography toremove the small amount of 3,4-dibromo byproduct using hexane,ethylacetate (2:1 to 1:1 gradient) as eluent yielding bromohydrin C as awhite solid (2.00 g, 78%). HPLC: 100% at 3.42 min. (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% methanol/water with 0.2% H₃PO₄ linear gradientover 4 min., 4 mL/min., UV Detection at 220 nm. HNMR: CDCl₃ 1.19, t,J=7.1 Hz(3H); 1.32, s (1H); 1.43, s (6H); 4.07, d, J=9.4 Hz(2H); 4.31,q, J=5.4 Hz(2H); 4.90, d, J=9.6 Hz(1H); 8.42, dd, J=2.4 and 1.1 Hz (1H);8.77, d, J=1.8 Hz(1H).

Preparation of D:

Potassium hydroxide pellets (1.48 g, 26.3 mmol) were added to a stirredsolution ofethyl-6-carboxy-trans-4-hydroxy-3-bromo-3,4-dihydro-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(1.56 g, 4.74 mmol) in ether/ethylacetate (30/10 mL) at ambienttemperature. After 4 h the slurry was filtered through a sintered glassfunnel and the solvents removed in vacuo yielding epoxide D (1.03 g,87%) as a white powder. HPLC: 88% at 3.11 min. (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% methanol/water with 0.1% TFA linear gradientover 4 min., 4 mL/min., UV Detection at 220 nm. HNMR: CDCl₃ 1.40,s(3H);1.40, t, J=7.1 Hz(3H); 3.59, d, J=4.2 Hz(1H); 4.01, d, J=4.2 Hz(1H);4.39, q, J=7.1 Hz(2H); 8.33, d, J=2.4 Hz (1H); 8.85, d, J=2.2 Hz(1H).

Preparation of E:

Ethyl-6-carboxy-3,4-epoxide-3,4-dihydro-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(1.34 g, 5.36 mmol) was dissolved in ethanol (15 mL). Concentratedammonium hydroxide (15 mL) was added and the solution heated to 80° C.under positive pressure of nitrogen. Two further aliquots of 5 mLammonium hydroxide were added at 15 minute intervals and the solutionmaintained at 80° C. for a further 4 h. On cooling, the solvents wereremoved and the white solid redissolved in dichloromethane (100 mL) andwashed with water (3×50 mL). The organic phase was dried over sodiumsulfate, decanted and the dried in vacuo yielding a white solid productE (1.39 g, 97%) which was sufficiently pure to be used without furtherpurification. HPLC: 92% at 1.97 min. (YMC S5 ODS 4.6×50 mm Ballisticcolumn) 10-90% methanol/water with 0.1% TFA linear gradient over 4 min.,4 mL/min., UV Detection at 220 nm.

Preparation of F:

To a solution ofethyl-6-carboxy-trans-4-amino-3-hydroxy-3,4-dihydro-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(E, 1.39 g, 5.23 mmol) in dichloromethane/triethylamine (15 mL/2 mL) wasadded 4-ethylbenzenesulfonyl chloride (1.28 g, 6.27 mmol) dropwise atambient temperature. After 2 h a further 0.5 mL of TEA was added and thereaction mixture stirred for 12 h. The volume of dichloromethane wasreduced under reduced pressure and the crude solution loaded directlyonto a silica gel column and eluted with hexane/ethylacetate/methanol(2:2:1) yielding F as a white solid (1.18 g, 52%). HPLC: 89% at 3.98min. (YMC S5 ODS 4.6×50 mm Ballistic column) 40-90% methanol/water with0.2% H₃PO₄ linear gradient over 4 min., 4 mL/min., UV Detection at 220nm. HNMR: CDCl₃ 1.27,s(3H); 1.29, t, J=7.6 Hz(3H); 1.37, t, J=7.1Hz(3H); 1.56, s(3H); 2.76, q, J=7.6 Hz(2H); 3.72, d, J=9.5 Hz(1H); 4.31,q, J=7.1 Hz(2H); 4.33, d, J=7.4 Hz(1H); 7.40, d, J=8.1 Hz(2H); 7.86,s(1H); 7.90, d, J=8.1 Hz(2H); 8.70, s(1H).

Preparation of G:

A solution ofethyl-6-carboxy-trans-N-[4-ethylphenylsulfonyl]-4-amino-3-hydroxy-3,4-dihydro-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(F, 477 mg, 1.10 mmol) in ethylene glycol/tetrahydroduran (6.6/2.2 mL)and aqueous potassium hydroxide (6.6 mL, 30% by weight) was heated to100° C. for 12 h. The cooled solution was diluted with water (ca. 200mL), the pH adjusted to 4-S with 5% hydrochloric acid and extractedsuccessively with dichloromethane (3×50 mL) and ethylacetate (2×50 mL).The combined organic portions were dried over sodium sulfate, decantedand the solvents removed. G was obtained as a pale brown powder (518 mg,116%) sufficiently pure to be used without further purification. HPLC:93% at 3.53 min. (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%methanol/water with 0.2% H₃PO₄ linear gradient over 4 min., 4 mL/min.,UV Detection at 220 nm.

Preparation of H:

To a solution of6-carboxy-trans-N-[4-ethylphenylsulfonyl]-4-amino-3-hydroxy-3,4-dihydro-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(G, 25 mg, 0.062 mmol) in acetonitrile (2 mL) containing TEA (3 drops)was added bromo-tris-pyrrolidinophosphonium hexafluorophosphate (31 mg,0.066 mmol). After 5 min., (S)-2-phenyl-1-propylamine (8 mg, 1 drop) wasadded and the resulting solution stirred at ambient temperature for 12h. The crude reaction mixture was purified directly by preparative HPLC(YMC PACK S5 ODSA 20×100 mm column Reversed phase C18) 23-90%methanol/water with 0.1% TFA linear gradient over 10 min. 5 min. holdtime, 20 mL/min., UV Detection at 220 nm yielding the TFA salt of N as awhite amorphous solid (18.4 mg, 47%). HPLC: 97% at 4.24 min. (YMC S5 ODS4.6×50 mm Ballistic column) 10-90% methanol/water with 0.2% H₃PO₄ lineargradient over 4 min., 4 mL/min., UV Detection at 220 nm. LCMS: 97% at3.90 min. (YMC 5S ODS 4.6×50 mm Ballistic column) 10-90% methanol/waterwith 0.1% TFA linear gradient over 4 min., 4 mL/min., UV Detection at220 nm, M+1 524. HNMR: CDCl 1.06, s(3H); 1.09, t, J=7.6 Hz(3H); 1.12, d,J=7.0 Hz(3H); 1.26, s(3H); 2.56, q, J=7.6 Hz(2H); 2.91, m(1H); 3.32,m(2H); 3.38, d, J=8.9 Hz(1H); 4.21, dd, J=8.7 and 0.8 Hz(1H); 7.06, m(4H); 7.21, d, J=8.3 Hz(2H); 7.67, d, J=7.9 Hz(2H); 7.91, m (1H); 8.14,s (1H).

The following compounds were synthesized by the procedures described inExample 206.

Example Structure mass spec m/z 207

510 (M + H) 208

460 (M + H) 209

524 (M + H) 210

593 (M + H) 211

593 (M + H) 212

593 (M + H) 213

539 (M + H) 214

510 (M + H) 215

560 (M + H) 216

540 (M + H) 217

540 (M + H) 218

524 (M + H) 219

567 (M + H) 220

548 (M + H)

Example Structure Mass spec M/Z 221

558 (M + 1) 222

535 (M + 1) 223

500 (M + 1) 224

567 (M + 1) 225

525 (M + 1) 226

512 (M + 1) 227

512 (M + 1) 228

525 (M + 1) 229

496 (M + 1) 230

503 (M + 1) 231

553 (M + 1) 232

525 (M + 1) 233

565 (M + 1) 234

511 (M + 1) 235

525 (M + 1) 236

505 (M + 1) 237

503 (M + 1) 238

549 (M + 1) 239

589 (M + 1) 240

511 (M + 1) 241

542 (M + 1) 242

554 (M + 1) 243

596 (M + 1) 244

514 (M + 1) 245

508 (M + 1) 246

510 (M + 1)

EXAMPLE 247

Preparation of J:

To a stirred solution of 2-Fluoro-5-methyl aniline (187 m g, 1.50 mmol)in anhydrous dichloromethane (4 mL) containing triethylamine (150 mg,1.48 mmol) at ambient temperature was added acetyl chloride dropwise(130 mg, 1.64 mmol, 1.10 equivalent). After 14 h the solvents wereremoved in vacuo yielding a white solid product (271 mg, quantative).HPLC: 96% at 2.67 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm. LCMS: 97% at 2.21 min (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% MeOH/water with 0.1% TFA linear gradient over 4min, 4 mL/min, UV Detection at 220 nm, M+1 168.

The crude N-acetamide (162 mg, 0.96 mmol) was dissolved in anhydrousacetonitrile (4 mL) and a solution of Lithium Aluminum Hydride was added(1.6 mL, 1.6 mmol, 1.0M in THF) dropwise. When evolution of hydrogen hadceased, the slurry was heated to 70° C. for 1 h, allowed to cool andthen transferred to a 2.5 g C18 cartridge which had been pre-washedsuccessively with 7.5 mL Water, 7.5 mL MeOH and 7.5 mL dichloromethane.The N-Ethylated product, J, was eluted with 7.5 mL of dichloromethaneand the solvents removed to yield a pale yellow residue (50 mg, 34%).HPLC: 80% at 1.74 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm. LCMS: 80% at 1.62 min (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% MeOH/water with 0.1% TFA linear gradient over 4min, 4 mL/min, UV Detection at 220 nm, M+1 154.

Preparation of K:

Compound K was synthesized and purified using the procedure describedfor the preparation of H in Example 206. LCMS: 80% at 1.62 min (YMC S5ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.1% TFA lineargradient over 4 min, 4 mL/min, UV Detection at 220 nm, M+1 154.

The following compounds were synthesized by the procedures described inExample 247

Example Structure Mass spec M/Z 248

524 (M + 1) 249

544 (M + 1) 250

554 (M + 1) 251

540 (M + 1) 252

524 (M + 1) 253

540 (M + 1) 254

546 (M + 1) 255

542 (M + 1) 256

554 (M + 1) 257

538 (M + 1) 258

542 (M + 1) 259

554 (M + 1) 260

538 (M + 1) 261

576 (M + 1) 262

560 (M + 1) 263

538 (M + 1) 264

585 (M + 1)

EXAMPLE 265

Preparation of L and Q:

At 20° C., Pyridine diborane complex (0.032 mL, 0.317 mmol) was addeddropwise with stirring to a slurry of amino-alcohol, B (100 mg, 0.38mmol) and butanal (28 mg, 0.39 mmol) in anhydrous methanol (1.0 mL)containing powdered 4A molecular sieves (34 mg). After 14 h, 5% HCl wasadded (10 mL) and the resulting solution stirred for 10 min thenadjusted to pH11 by addition of 5% NaOH and extracted intodichloromethane (3×20 mL). The combined extracts were dried over Na₂SO₄,decanted, concentrated, redissolved in 1 mL of acetone and applieddirectly to a preparative silica gel TLC plate, (20×20 cm, 1 mmthickness, 254 nm UV indicator) eluting with 2:1 hexane:acetone. L wasisolated as the more polar product (R_(f) 0.3, 63 mg, 52%) LCMS: R_(T)2.53 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with0.1% TFA linear gradient over 4 min, 4 mL/min, UV Detection at 220 nm,M+1 323. Q was isolated a the less polar product (R_(f) 0.4, 41 mg, 29%)LCMS: R_(T) 2.88 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.1% TFA linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm, M+1 379.

Preparation of M:

To a solution ofEthyl-6-carboxy-trans-N-[n-butyl]-4-amino-3-hydroxy-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(L, 63 mg, 0.20 mmol) in CH₂Cl₂/TEA (4 mL/5 drops) was added EtPhSO₂Cl(44 mg, 0.22 mmol) at ambient temperature. The resulting solution wasstirred for 4 days, diluted with a further 40 mL of CH₂Cl₂ and passedthrough a short pad of silica (approx. 3 cm). The resulting pale yellowsolid (96 mg, crude quantative) was sufficiently pure to be hydrolyzeddirectly. LCMS: R_(T) 4.04 min (YMC S5 ODS 4.6×50 mm Ballistic column)10-90% MeOH/water with 0.1% TFA linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm, M+1 491.

Preparation of N:

A solution ofEthyl-6-carboxy-trans-N,N-[n-butyl-4-ethylphenylsulfonyl]-4-amino-3-hydroxy-2,2-dimethyl-2H-pyrano-[2,3b]-pyridine(M, 96 mg, 0.20 mmol) in ethylene glycol/THF (2.5/1.5 mL) and aqueousKOH (2.5 mL, 30% by weight) was heated to 110° C. for 3 h. The cooledsolution was diluted with water (ca. 200 mL), the pH adjusted to 4-5with 5% HCl and extracted successively with CH₂Cl₂ (3×50 mL) and EtOAc(2×50 mL). The combined organic portions were dried over Na₂SO₄,decanted and the solvents removed. N was obtained as a pale yellow oil(59 mg, 64%) sufficiently pure to be used without further purification.HPLC: >81% at 4.15 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm. LCMS: R_(T) 3.77 min (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% MeOH/water with 0.1% TFA linear gradient over 4min, 4 mL/min, UV Detection at 220 nm, M+1 463.

Preparation of P:

P was prepared in 35% isolated yield by the coupling describedpreviously for the preparation of H in Example N. The crude reactionmixture was purified by preparative HPLC (YMC PACK S5 ODSA 20×100 mmcolumn Reversed phase C18). 23-90% MeOH/water with 0.1% TFA lineargradient over 10 min 5 min hold time, 20 mL/min, UV Detection at 220 nmyielding the TFA salt of P as a white amorphous solid (13.3 mg, 35%).HPLC: 100% at 4.59 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm. LCMS: 99.1% at 4.24 min (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% MeOH/water with 0.1% TFA linear gradient over 4min, 4 mL/min, UV Detection at 220 nm, M+1 598. ¹HNMR: CDCl₃ 0.88,m(4H);1.20-1.24,m(9H); 1.26,s(3H); 1.46,s(3H); 2.73,d,J=7.6 Hz(2H);4.03,brs(7H); 5.05,s(1H); 7.0,t,J=8.0 Hz(1H); 7.15,t,J=8.0 Hz(1H);7.2-7.4,m(2H); 7.34,d,J=8.0 Hz(2H); 7.67,brd(2H); 7.9,brs(1H);8.27,s(1H).

Preparation of R:

R was prepared via KOH hydrolysis of ester Q in 68% yield as describedfor the preparation of N in Example N″. LCMS: 82% at 2.31 min (YMC S5ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.1% TFA lineargradient over 4 min, 4 mL/min, UV Detection at 220 nm, M+1 351.

Preparation of S:

S was prepared in 58% isolated yield by the coupling describedpreviously for the preparation of H in Example N. The crude reactionmixture was purified by preparative HPLC (YMC PACK S5 ODSA 20×100 mmcolumn Reversed phase C18) 23-90% MeOH/water with 0.1% TFA lineargradient over 10 min 5 min hold time, 20 mL/min, UV Detection at 220 nmyielding the TFA salt of S as a white amorphous solid (20.0 mg, 58%).HPLC: 96% at 3.49 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm. LCMS: 3.24 min (YMC S5 ODS 4.6×50 mm Ballisticcolumn) 10-90% MeOH/water with 0.1% TFA linear gradient over 4 min, 4mL/min, UV Detection at 220 nm, M+1 486. ¹HNMR: MeOD 0.92,brm(10H);1.17,t,J=7 Hz(3H); 1.25,s(3H); 1.3,brs(4H); 1.58,s(3H); 1.8-2.0 brm(2H);3.0-3.2,brm(2H); 3.6,m(3H); 4.23,d,J=8.8 Hz(1H); 4.9,s(2H); 7.05-7.40,m(4H); 8.20,d,J=1.6 Hz(1H); 8.30,brs(1H).

The following compounds were synthesized by the procedures described inExample 265

Example Structure Mass spec M/Z 266

648 (M + 1) 267

537 (M + 1)

EXAMPLE 268

Preparation of T:

N-Acetyl-6-bromo-2,2-dimethyl-1,2-dihydroquinoline was prepared fromcommercially available pBromoaniline in 3 steps as described.^(3,4)

Preparation of U:

At 0° C., mCpBA (4.08 g, assuming 50% active, 1.5 equivalents) was addedin 3 portions, 3 minutes apart to a vigorously stirred biphase solutionof N-Acetyl-6-bromo-2,2-dimethyl-1,2-dihydroquinoline (2.21 g, 7.92mmol) in dichloromethane/saturated NaHCO₃ 140 mL/200 mL. Stirring wasmaintained for 12 h as the slurry reached ambient temperature. Thereaction mixture was diluted with CH₂Cl₂ (50 mL) and the aqueous portionwashed further with CH₂Cl₂ (3×50 mL). The combined organic portions werewashed with saturated NaCl, (30 mL) dried over Na₂SO₄, decanted and thesolvents removed. U was obtained as a pale yellow oil (2.52 g, crudequantitative) sufficiently pure to be used without further purification.¹HNMR: CDCl₃ 1.18,s(3H); 1.90,s(3H); 2.10,s(3H); 3.40,d,J=4.3 Hz(1H);3.80,d,J=4.2 Hz(1H); 6.72,d,J=8.5 Hz(1H); 7.40,dd,J=2.4 Hz and J=8.6Hz(1H); 7.52,d,J=2.2 Hz.

Preparation of V:

A solution of epoxide U (442 mg, 1.44 mmol) in ethanol/concentratedNH₄OH (4 mL/4 mL) was heated to reflux (75° C.). A second portion ofconcentrated NH₄OH (4 mL) was added and the resulting brown solutionheated to reflux for a further 24 h. The solvents were removed underreduced pressure, the residue dissolved in methanol and purified byflash silica gel column chromatography (CH₂Cl₂ primed and eluted with10% methanol in CH₂Cl₂).N-Acetyl-6-bromo-4-amino-3-hydroxy-2,2-dimethyl-1,2,3,4-tetrahydroquinoline, V (238 mg, 53%) was obtained as a tan powder. HPLC: 83%at 3.00 min (YMC S5.ODS 4.6×50 mm Ballistic column) 10-90% MeOH/waterwith 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UV Detection at220 nm. ¹HNMR: CDCl₃ 1.16,s(3H); 1.29,s(3H); 2.15,s(3H); 3.56,d,J=9.6Hz(1H); 5.01,t,J=8.7 Hz(1H); 5.86,d,J=7.2 Hz(1H); 6.39,d,J=8.5 Hz(1H);7.14,dd,J=2.0 Hz and J=8.2 Hz(1H); 7.22,d,J=1.8 Hz.

Preparation of W:

Anhydrous NaOAc (162 mg, 1.98 mmol) was added to a stirred solution ofamino alcohol V (168 mg, 0.538 mmol) in Acetic Anhydride (2 mL) atambient temperature. The pale brown solution was heated to 90° C. for 3h, allowed to cool and poured into water (50 mL). The aqueous phase wasextracted with EtOAc (30 mL, 2×20 mL) and the combined organic portionswashed successively with saturated NaHCO₃ (2×20 mL) and water (20 mL)dried over Na₂SO₄, decanted and concentrated. The brown oil wasazeotroped with ether to yield a crude quantative amount of W as a tansolid. HPLC: >80% at 3.43 min (YMC S5 ODS 4.6×50 mm Ballistic column)10-90% MeOH/water with 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min,UV Detection at 220 nm.

Preparation of X:

In a thick walled glass reaction vessel with a teflon screw cap, asolution ofN-Acetyl-6-bromo-4-acetamido-3-hydroxy-2,2-dimethyl-1,2,3,4-tetrahydroquinoline, W (190 mg, 0.538 mmol) in N-Methylpyrrolidinone (2 mL)was added to CuCN (96 mg, 1.1 mmol). The vigorously stirred slurry washeated to 190-200° C. for 4 h, allowed to cool then poured into NH₄OH(50 mL). After 2 h the aqueous phase was extracted with EtOAc (3×20 mL)and the combined portions washed further with NH₄OH (3×20 mL) and water(2×20 mL). The solution was dried over Na₂SO₄, decanted and concentratedyielding a brown oil which was flash column chromatographed directlyover silica, hexane primed, hexane/EtOAc/MeOH (2:1:1) as eluent. X wasobtained as a pale brown oil (94 mg, 58%). HPLC: 2.56 min (YMC S5 ODS4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.2% H₃PO₄ lineargradient over 4 min, 4 mL/min, UV Detection at 220 nm. ¹HNMR: CDCl₃1.23,s(3H); 1.27,s(3H); 2.08,s(3H); 2.13,s(3H); 4.93,d,J=10 Hz(1H);5.30,t,J=10 Hz(1H); 5.86,d,J=9.5 Hz(1H); 6.48,d,J=8.4 Hz(1H);7.27,brd,J=8.0 Hz(1H); 7.27,brs.

Preparation of Y:

Concentrated H₂SO₄ (0.54 mL) was added to a solution ofN-Acetyl-6-cyano-4-acetamido-3-hydroxy-2,2-dimethyl-1,2,3,4-tetrahydroquinoline,(3.45 g, 11.5 mmol) in dioxane/water (35 mL/20 mL) and the solutionheated to reflux at 110° C. for 16 h. The cooled solution was pouredinto NH₄OH (30 mL) and extracted with EtOAc (3×20 mL). The combinedportions were dried over Na₂SO₄, decanted and concentrated yielding atan solid, Y (1.99 g, 80%). HPLC: 2.00 min (YMC S5 ODS 4.6×50 mmBallistic column) 10-90% MeOH/water with 0.2% H₃PO₄ linear gradient over4 min, 4 mL/min, UV Detection at 220 nm.

Preparation of A′:

A′ was prepared in 93% yield by KOH hydrolysis described previously forthe preparation of G in Example N. HPLC: 97% at 3.47 min (YMC S5 ODS4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.2% H₃PO₄ lineargradient over 4 min, 4 mL/min, UV Detection at 220 nm. LCMS: 3.14 min(YMC 5S ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.1% TFAlinear gradient over 4 min, 4 mL/min, UV Detection at 220 nm, M+1 405.¹HNMR: DMSO 1.13,s(3H); 1.16,t,J=7.2 Hz(2H); 1.21,s(3H); 2.68, q, J=7.6Hz (3H); 4.17, t, J=8.6 Hz(1H); 4.87, d, J=5.4 Hz(1H); 6.46, d , J=9.8Hz(1H); 6.53, brs (1H); 7.36, d, J=8.2 Hz(2H); 7.49, dd, J=1.6 Hz andJ=8.4 Hz(1H); 7.79, d, J=8.4 Hz(2H); 7.80, d, J=1.6 Hz(1H); 7.86, d,J=8.4 Hz (1H).

Preparation of B′:

B′ was prepared in 30% isolated yield by the coupling describedpreviously for the preparation of H in Example N. The crude reactionmixture was purified by preparative HPLC (YMC PACK S5 ODSA 20×100 mmcolumn Reversed phase C18) 23-90% MeOH/water with 0.1% TFA lineargradient over 10 min 5 min hold time, 20 mL/min, UV Detection at 220 nmyielding B′ as a white amorphous solid (28.7 mg, 30%). HPLC: 97% at 4.02min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with 0.2%H₃PO₄ linear gradient over 4 min, 4 mL/min, UV Detection at 220 nm.LCMS: 4.02 min (YMC S5.ODS 4.6×50 mm Ballistic column) 10-90% MeOH/waterwith 0.1% TFA linear gradient over 4 min, 4 mL/min, UV Detection at 220nm, M+1 562. ¹HNMR: MeOD 1.11, s(3H); 1.25, t, J=7.4 Hz (3H); 1.25,s(3H); 2.71, q, J=7.2 Hz(2H); 3.50, d, J=8.5 Hz(1H); 4.28, d, J=8.5Hz(1H); 4.58, s(2H); 6.54, d, J=8.4 Hz(1H); 7.33, s(2H); 7.38, d, J=8.4Hz(2H); 7.5-7.6, m(3H); 7.89, s(1H); 7.89, d, J=8.4 Hz.

REFERENCE

3. Atwal, Karnail. (Squibb, E. R., and Sons, Inc., USA). Application: US91-776921 911015

4. Williamson, N. M; March, D. R; Ward, D. A; Tetrahedron Lett. 1995,36(42) 7721-4.

The following compounds were synthesized by the procedures described inExample 268

Example Structure Mass spec M/Z 269

648 (M + 1) 270

540 (M + 1) 271

556 (M + 1) 272

538 (M + 1) 273

547 (M + 1) 274

498 (M + 1) 275

565 (M + 1) 276

495 (M + 1) 277

523 (M + 1) 278

515 (M + 1) 279

538 (M + 1) 280

508 (M + 1) 281

496 (M + 1) 282

510 (M + 1) 283

560 (M + 1) 284

498 (M + 1) 285

523 (M + 1) 286

494 (M + 1) 287

565 (M + 1) 288

508 (M + 1) 289

522 (M + 1) 290

512 (M + 1) 291

551 (M + 1) 292

551 (M + 1) 293

591 (M + 1) 294

523 (M + 1) 295

552 (M + 1) 296

563 (M + 1) 297

509 (M + 1) 298

567 (M + 1) 299

537 (M + 1) 300

523 (M + 1) 301

517 (M + 1) 302

515 (M + 1) 303

501 (M + 1) 304

547 (M + 1) 305

609 (M + 1) 306

587 (M + 1) 307

588 (M + 1) 308

590 (M + 1) 309

509 (M + 1) 310

546 (M + 1) 311

522 (M + 1) 312

538 (M + 1) 313

591 (M + 1) 314

522 (M + 1)

EXAMPLE 315

Preparation of A:

Compound A was prepared as described in example 268.

Preparation of C:

Tetramethylfluoroformamidinium hexafluorophosphate (21 mg, 0.08 mmol)was added to a stirred slurry of A (27 mg, 0.066 mmol) in CH₂Cl₂ (2 mL).Triethylamine (2 drops) was added and the resulting solution stirred for1 h then a second portion of TFFH was added (21 mg, 0.08 mmol). Thesolution was diluted with 10 mL of CH₂Cl₂, passed through a short pad ofsilica and concentrated. NH₄OH was added to the residue and the crudesolution purified by preparative HPLC (YMC PACK S5 ODSA 20×100 mm columnReversed phase C18) 23-90% MeOH/water with 0.1% TFA linear gradient over10 min 5 min hold time, 20 mL/min, UV Detection at 220 nm. HPLC: 95% at2.92 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% MeOH/water with0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UV Detection at 220 nm.LCMS: 2.95 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% MeOH/waterwith 0.1% TFA linear gradient over 4 min, 4 mL/min, UV Detection at 220nm, M+1 404.

EXAMPLE 316

Preparation of A:

Compound A was prepared as described in example 1.

Preparation of B:

Tetramethylfluoroformamidinium hexafluorophosphate (24 mg, 0.09 mmol)was added to a stirred slurry of benzopyran (34 mg, 0.084 mmol) inCH₂Cl₂ (2 mL). Triethylamine (3 drops) was added and the resultingsolution stirred at ambient temperature for 12 h. The solvents wereremoved and the crude solution purified by preparative HPLC (YMC PACK S5ODSA 20×100 mm column Reversed phase C18) 23-90% MeOH/water with 0.1%TFA linear gradient over 10 min 5 min hold time, 20 mL/min, UV Detectionat 220 nm. D′ was obtained as a pale yellow oil (42 mg, 92%). HPLC: 95%at 4.36 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90% MeOH/waterwith 0.2% H₃PO₄ linear gradient over 4 min, 4 mL/min, UV Detection at220 nm. LCMS: 3.96 min (YMC S5 ODS 4.6×50 mm Ballistic column) 10-90%MeOH/water with 0.1% TFA linear gradient over 4 min, 4 mL/min, UVDetection at 220 nm, M+1 541. ¹HNMR: MeOD 0.94,brs(3H); 1.05, s(3H);1.10, t, J=7.0 Hz(2H); 1.24, s(3H); 2.57, q, J=6.6 Hz(2H); 3.04, q,J=8.0 Hz(2H); 3.41, d, J=8.0 Hz(1H); 4.18, d, J=8.0 Hz(1H); 4.7,brs(2H); 6.4-7.3, m(6H); 7.73, d, J=8.0 Hz.

EXAMPLE 317

Preparation of A:

The polystyrene resin bound aldehyde was prepared as described inSarantakis, D.; Bicksler, J. J.; Tetrahedron Letters 1997, 38 (42),7325-7328.

Preparation of B

The benxopyran ester was synthesized from the the example 1 part Acompound by standard methods.

Preparation of C:

The resin bound aldehyde (10 g, 1 mmol/g loading, 10 mmol) was suspendedin 75 mL tetrahydrofuran, 25 mL methanol and 25 mLtrimethylorthoformate. Acetic acid (2 mL) was added followed by compoundB (3.77 g, 15 mmol) and the reaction was shaken for 16 hrs. The mixturewas then filtered and washed with THF then methanol and dried to provide11.64 g of resin.

Preparation of D:

The resin C (100 mg, 0.087 mmol) was suspended in 1 mL ofdichloromethane and N,N-diisopropylethylamine (23 μL, 0.13 mmol) and3-toluenesulfonyl chloride (0.5 mL, 0.26 M in dichloromethane, 0.13mmol) were added. The reaction was shaken for 16 hrs. The mixture wasthe filtered and washed with dichloromethane then tetrahydrofuran anddried in vacuo.

Preparation of E:

The resin D was suspended in 2 mL 50% methanol in tetrahydrofuran andsodium hydroxide was added (174 μL, 1.74 mmol). The reaction was heatedto 40° and shaken for 24 hrs. The mixture was filtered the washed with50% methanol in Tetrahydrofuran the with methanol and dried in vacuo.

Preparation of F:

The resin E was suspended in a solution of(S)-(+)-2-(2,6-xylidinomethyl)pyrrolidine [70371-56-1] (1 mL, 0.43 M indichloroethane, 0.43 mmol) and diisopropylethylamine (151 μL, 0.87 mmol)was added. Bromo-tris-pyrrolidinophosphonium hexafluorophosphate(PyBroP) (1 mL, 0.43 M in dichloroethane, 0.43 mmol) was added and thereaction was shaken for 24 hrs at 70°. The mixture was filtered thewashed with dichloromethane and dried in vacuo.

Preparation of G:

The resin F was suspended in 2 mL of 50% trifluoroacetic acid indichloromethane. The reaction was shaken for 1 hr the filtered andwashed with dichloromethane. The filtrate was combined and the solventremoved. The residue was dissolved in 1 mL of acetonitrile and loadedonto a strong cation exchange cartridge (Varian 3 g SAX). The cartridgewas washed with 10 mL 0.05 M ammonia methanol then eluted with 10 mL of1 M ammonia methanol. The solvent was removed from the 1 M ammoniafraction to provide 26 mg (52%) of a white solid.

The following examples were synthesized by the methods described inexample 317 except that the compounds that are not basic were purifiedby dissolving the residue in acetonitrile and loading it onto a mixedSCX and SAX cartridge and eluting the product with acetonitrile.

Example Structure Mass spec M/Z 318

578 (M + H) 319

586 (M + H) 320

538 (M + H) 321

592 (M + H) 322

566 (M + H) 323

537 (M + H) 324

533 (M + H) 325

494 (M + H) 326

481 (M + H) 327

546 (M + H) 328

632 (M + H) 329

632 (M + H) 330

640 (M + H) 331

592 (M + H) 332

646 (M + H) 333

620 (M + H) 334

591 (M + H) 335

587 (M + H) 336

548 (M + H) 337

600 (M + H) 338

648 (M + H) 339

648 (M + H) 340

656 (M + H) 341

608 (M + H) 342

662 343

636 (M + H) 344

607 (M + H) 345

613 (M + H) 346

603 (M + H) 347

551 (M + H) 348

615 (M + H) 349

614 (M + H) 350

614 (M + H) 351

622 (M + H) 352

574 (M + H) 353

628 (M + H) 354

602 (M + H) 355

573 (M + H) 356

517 (M + H) 357

581 (M + H) 358

682 (M + H) 359

682 (M + H) 360

690 (M + H) 361

642 (M + H) 362

696 (M + H) 363

670 (M + H) 364

637 365

585 (M + H) 366

649 (M + H) 367

668 (M + H) 368

668 (M + H) 369

676 (M + H) 370

682 (M + H) 371

656 (M + H) 372

633 (M + H) 373

632 (M + H) 374

571 (M + H) 375

635 (M + H) 376

718 (M + H) 377

718 (M + H) 378

726 (M + H) 379

678 (M + H) 380

732 (M + H) 381

706 (M + H) 382

683 (M + H) 383

673 (M + H) 384

673 (M + H) 385

621 (M + H) 386

685 (M + H) 387

629 (M + H) 388

628 (M + H) 389

636 (M + H) 390

588 (M + H) 391

642 (M + H) 392

616 (M + H) 393

587 (M + H) 394

593 (M + H) 395

583 (M + H) 396

544 (M + H) 397

531 (M + H) 398

595 (M + H)

What is claimed is:
 1. A compound having the structure

or pharmaceutically acceptable salts thereof, prodrug esters thereof, orall stereoisomers thereof, wherein A, B and D are each CH; X¹ is

 (where n is 1, 2 or 3), NR⁶ or

 wherein the N atom is linked to the aromatic ring; (where R³ and R⁴ areindependently H, alkyl, arylalkyl or cycloalkyl, or R³ and R⁴ can betaken together with the carbon to which they are attached to form a 5 to8 carbon containing ring; and R⁶ is H, alkyl, alkenyl, aryl, arylalkyl,cycloalkyl or cycloalkylalkyl); R is H, alkyl, alkenyl, aryl, arylalkyl,heterocycloalkyl, cycloalkyl, or cycloalkylalkyl; R¹ is alkyl,arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl,

 (where R^(5a) can be any of the R⁵ groups), cycloalkyl, cycloalkylalkylor

 (where R⁶ and R⁷ are independently selected from H, aryl, alkyl,arylalkyl or cycloalkyl, or R⁶ and R⁷ can be taken together with thenitrogen atom to which they are attached to form a 5 to 8 memberedring); or R and R¹ can be taken together with the —N—S— atoms to form a5- to 8-membered ring; X² is a single bond,

 or —O— (where R⁸ is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl orcycloalkylalkyl); R² is H, alkyl, arylalkyl,

 or

 (where R¹⁰ and R¹¹ are independently selected from H, alkyl, arylalkylor cycloalkyl, or R¹⁰ and R¹¹ can be taken together with the nitrogen towhich they are attached to form a 5- to 8-membered ring); and Q is

 or

 (where R¹² is alkyl, arylalkyl, aryl,

 heterocycle, heterocycloalkyl,

 (where R¹⁴ can be any of the R⁵ groups), alkoxy, CF₃, aryloxy,arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R¹⁵ and R¹⁶ areindependently selected from H, alkyl, arylalkyl, aryl, heterocyclo,cycloalkyl, amino, aminoalkyl, or heterocycloalkyl, or R¹⁵ and R¹⁶ canbe taken together with the nitrogen to which they are attached to form a5- to 8-membered ring which may optionally contain an additionalnitrogen atom in the ring and/or an amino group or an aminoalkyl groupattached to the ring); and R¹³ is

 (wherein this moiety is as defined with respect to R¹²).
 2. Thecompound as defined in claim 1 having the structure


3. The compound as defined in claim 1 having the structure

or


4. The compound as defined in claim 1 having the formula


5. The compound as defined in claim 1 having the structure

or


6. The compound as defined in claim 1 having the structure


7. The compound as defined in claim 1 wherein R is H; R¹ is aryl oralkyl; X² is O or a single bond; R² is H; Q is

 or

 where R¹⁵ and R¹⁶ are independently H, aryl, aralkyl or aminoalkyl; X¹is

A and B and D are each CH.
 8. The compound as defined in claim 1 havingthe structure


9. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier therefor.
 10. Apharmaceutical composition comprising a compound as defined in claim 1in combination with one or more components selected from the groupconsisting of cyclooxygenase inhibitors, fibrinogen antagonists,diuretics, angiotensin converting enzyme inhibitors, angiotensin IIantagonists, thrombolytic agents, calcium channel blocking agents,thromboxane receptor antagonists, prostacyclin mimetics andphosphodiesterase inhibitors.
 11. A method for preventing or treatingcardiac arrhythmia or atrial arrhythmia, which comprises administeringto a mammalian species in need of treatment a therapeutically effectiveamount of a compound which has the structure

or pharmaceutically acceptable salts thereof, prodrug esters thereof, orall stereoisomers thereof, wherein A, B and D are each independently CH;X¹ is

 (where n is 1, 2 or 3), NR⁵ or

 wherein the heteroatom in each of the above groups is linked to thearomatic ring; (where R³ and R⁴ are independently H, alkyl, arylalkyl orcycloalkyl, or R³ and R⁴ can be taken together with the carbon to whichthey are attached to form a 5 to 8 carbon containing ring; and R⁵ is H,alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl); R is H,alkyl alkenyl, aryl, arylalkyl, heterocycloalkyl, cycloalkyl, orcycloalkylalkyl; R¹ is alkyl arylalkyl, aryl, alkenyl, heterocyclo,heterocycloalkyl,

 (where R^(5a) can be any of the R⁵ groups), cycloalkyl, cycloalkylalkylor

 (where R⁶ and R⁷ are independently selected from H, aryl, alkyl,arylalkyl or cycloalkyl, or R⁶ and R⁷ can be taken together with thenitrogen atom to which they are attached to form a 5 to 8 memberedring); or R and R¹ can be taken together with the —N—S— atoms to form a5- to 8-membered ring; X² is a single bond,

 or —O— (where R⁵ is H, alkyl, alkenyl aryl, arylalkyl, cycloalkyl orcycloalkylalkyl); R² is H, alkyl, arylalkyl,

 or

 (where R¹⁰ and R¹¹ are independently selected from H, alkyl, arylalkylor cycloalkyl, or R¹⁰ and R¹¹ can be taken together with the nitrogen towhich they are attached to form a 5- to 8-membered ring); and Q is

 or R¹²-heterocycle (where R¹² is alkyl, arylalkyl, aryl,

 heterocycle, heterocycloalkyl,

 (where R¹⁴ can be any of the R⁵ groups), CF₃, alkoxy, aryloxy,arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R¹⁵ and R¹⁶ areindependently selected from H, alkyl, arylalkyl, aryl, heterocyclo,amino, aminoalkyl, cycloalkyl or heterocycloalkyl, or R¹⁵ and R¹⁶ can betaken together with the nitrogen to which they are attached to form a 5-to 8-membered ring which may optionally contain an additional nitrogenatom in the ring and/or an amino group or an aminoalkyl group attachedto the ring); and R¹³ is

 (wherein this moiety is as defined with respect to R¹²).